The Ets-domain family of transcription factors is comprised of several proteins that are inviolved in controlling key cellular events such as proliferation, differentiation, and development. Their activity is often regulated by signal transduction pathways involving MAP kinases and, in regard to disease, the deregulation or mutation of Ets proteins is found primarily in cancers.
While the Ets family is very diverse in protein sequence, all of the family members share a DNA binding domain known as the Ets-domain, so called because it resembles the protein product of the v-ets oncogene of the E26 avian erythroblastosis virus. Through this motif, the Ets family proteins bind the promoter region of various genes at the consensus sequence, GGA, thereby acting as either repressors or activators through DNA-protein interactions and/or protein-protein interactions. All members of the family, except one, bind to DNA as a monomer and based on the homology within the Ets domain the Ets proteins have been further divided into subfamilies (Dittmer and Nordheim, Biochim. Biophys. Acta, 1998, 1377, F1-11).
Ets-2, the second of the two-member Ets subfamily of transcription factors to be characterized (Ets-1 being the other member), was originally identified based on its homology to the mouse Ets-2 gene and has been implicated in the regulation of cellular proliferation ztnd differentiation (Watson et al., Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 7862-7866). Ets-2 is located within a chromosomal region (21q22.3) known to undergo translocations associated with malignancies (Watson et al., Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 7862-7866). Chromosome 21 is triplicated in Down's syndrome and it is assumed that Ets-2 is responsible for the skeletal abnormalities seen in this disorder as transgenic mice that overexpress Ets-2 show similar skeletal defects (Sumarsono et al., Nature, 1996, 379, 534-537).
Upregulation of Ets-2 expression has been found in several cancers including lymphoblastic leukemia (Santoro et al., Cancer Genet. Cytogenet., 1992, 58, 71-75), hepatocellular carcinoma (Bhat et al., Proc. Natl. Acad. Sc.i U.S.A., 1987, 84, 3161-3165; Liao et al., Cancer Lett., 1996, 100, 215-221), cervical carcinoma (Simpson et al., Oncogene, 1997, 14, 2149-2157), breast cancer (Sapi et al., Cancer Res., 1998, 58, 1027-1033) and rheumatoid arthritis (Dooley et al., Ann. Rheum. Dis., 1996, 55, 298-304).
Ets-2 has recently been shown to activate the promoters for urokinase plasminogen activator (uPA) and metalloproteinases in response to epidernal growth factor stimulation. Since elevated levels of these gene products have been associated with the processes of invasion and metastasis in breast cancers, Ets-2 has therefore been linked to the cancer phenotype (Watabe et al., Int. J. Cancer, 1998, 77, 128-137).
Currently, there are no known therapeutic agents that effectively inhibit the synthesis of Ets-2. Consequently, there remains a long felt need for agents capable of effectively inhibiting Ets-2 function.
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of Ets-2 expression.